Pharmacogenetics

Each person differs in their response to a drug. Even when given the same dose of a drug, patients can vary in the blood level of the drug they achieve, the type and severity of possible side-effects, and the effectiveness of the drug.

Differences in response to antiretroviral (ARV) treatment can result from a number of factors related to the HIV virus and to the host. These include the genetic make-up of the virus and the patient’s age, gender, ethnicity, and co-morbid conditions, as well as possible interactions with food, other medications, herbal products, and recreational drugs. It is becoming increasingly evident that human genetics also play an important role in the outcome of medical interventions.

It is estimated that 20 to 95% of the variability in the distribution and effects of drugs is caused by genetic variation.¹ Variations in genes bring about changes in the level or activity of the cell’s components that are responsible for the absorption, distribution, and metabolism of the drugs, leading to changes in drug levels. These variations can also determine the risk of a patient experiencing side-effects or toxicity.

Pharmacogenetics is the study of variation in human genes on responses to drugs. However, despite being an area of research interest for over fifty years, optimistic predictions that doctors would be able to use the information from the study of pharmacogenetics and the sequencing of the human genome to tailor treatment for patients based on their genetic make-up have only been met in part. While a few examples of clear links between genetic variants and differences in drug responses have been discovered, the routine use of genetic testing to guide treatment choices remains a distant prospect for many areas of medicine.

HIV medicine has not escaped this optimism, with a large number of studies claiming to show strong links between genetic variation and the metabolism or absorption of ARV drugs and the severity of side-effects. However, the only genetic test that has been introduced into HIV treatment is one that predicts which patients are likely to suffer a hypersensitivity reaction to abacavir (Ziagen), a nucleoside reverse transcriptase inhibitor (NRTI).

The likelihood of other tests being introduced will depend on the results of association studies being confirmed in future clinical trials. However, studies to link genetic variation to the effects of drugs are dogged by complex interactions between genes and non-genetic sources of variation, as well as technical difficulties, leading to high rates of false positives, disagreements in the results of similar studies, and difficulties in interpreting study findings.

This chapter includes background information on genes, inheritance, and the study of genetics before summarising research into genetic variation and response to ARVs. The role of human genetics in the rate of HIV disease progression is discussed in Non-infectious co-factors in The immune system and HIV.